Cardiac Excitation-Contraction Coupling

Cells depolarize the Ca2+ runs through T tubules and then go to dihydropyidine receptors (trigger and subtype of the L type Ca2+ channels) and Ca2+ is released from SR and then causes contraction and once reuptake through SR relaxation occurs but also can have Ca2+ exit the cell through the Na/Ca exchanger (not as much)

Circuit pump: phopholamban is associated with circuit pump and inhibits it; in cases of high cAMP and PKA activity it becomes phosphorylated, the phospholamban drops away and the circuit can go to at a higher rate which increases the ability to relax and Ca2+ reuptake

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Cardiac Excitation-Contraction Coupling in Heart Failure

Pathologic changes: high sympathetic activity continuously

Lose t tubules and L type Ca2+ channels (DHPR) when Ca2+ comes through you get less trigger signal leading to Ca2+ transient and amplitude and reduced contraction and reduced reuptake because phospholamban doesn’t get phosphorylated as much so impaired relaxation, an important part of heart failure

VSM: key difference is increase cAMP causes relaxation via inhibition of MLCK, which in cardiomyocytes if increased cAMP you will increase contraction/inotropy

Alpha vs. Beta Agonists: IP3 and cAMP

Alpha 1 = IP3 connection = vasoconstriction

Inotropy is enhanced by increased cAMP and IP3, but IP3 to a lesser extent

Increase in cAMP, decrease in IP3, and increase in cGMP (NO production) = dilation of vasculature

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Systolic vs. Diastolic Dysfunction

Systolic failure where you lose inotropy, it reduces the ESV relationship which tells how much pressure you can have for a given empty volume; lose ability to contract you can only achieve the higher pressures at much higher volumes by increasing overall preload (EDV) and that is the basis of dilation and heart failure; reduced EF

Diastolic failure: untreated HTN and get strong stiff ventricle, it is difficult to fill it out and decreases compliance from stiffness and filling pressures are going to be much greater; preserved EF

Causes of Systolic Dysfunction

Systolic PV Loop

If you lose the slope, you achieve the ESP or empty volume, at much higher volumes; increase in compliance and moves loop to the right; increases ESV, more so than EDS so get decrease in SV = reduces EF

Increase of wedge pressure increases risk for pulmonary edema

Increases wall stress thus increasing myocardial O2 demand

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Acute and Chronic Compensation for Increased ESV

ACUTE: increased ESV (due to reduced SV) is added to normal venous return thereby adding to next cycle and get increased EDV

Diastolic Dysfunction and Ventricular Compliance

Diastolic dysfunction causes decrease in compliance meaning have higher pressures for any given EDV

As it becomes stiffer and stiffer it takes more pressure to get the same volume

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Diastolic Dysfunction PV Loop

See upshift in overall EDPVR because of reduced compliance so it takes much increased pressure to fill the volume (EDV) and this puts you at greater risk for pulmonary edema or pericardial effusion

Increase in ESV gives you a much increased EDP, which greatly increase your pulmonary capillary wedge pressure (final filling pressure of L ventricle) and ESV may decrease because of decreased afterload and if lower CO then get lower arterial pressure and reduced pressure in aorta and get reduced pressure in ESV

Long term effects: stimulates hypertrophy of heart and vessels, increases sympathetic drive and arterial pressure

Overtime: cardiac hypertrophy and negative outcomes due to prolonged induction of the system

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Opposition to Sympathetic Innvervation

Opposing system: natriuretic system

Sympathetic drive increases RAAS activation = bad for heart failure as it progress, but ANP and BNP opposes it

When myocytes become stretched chronically they release ANP to counteract the effects the of RAAS system; increase GFR to get diuresis and natriuresis and decreases central venous pressure that reduces CO and relaxes systemic arterial system to reduce pressure; also reduces blood volume and preload dependent CO